The present invention is directed to methods and compositions for transdermal administration. In particular, the present invention is directed to methods and compositions for the transdermal administration of an amine containing compound having biphasic solubility and/or an agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., a muscle relaxant, to relieve pain.
It is believed that damage to somatic sensory nerves causes a somatic sensory loss. Such damage can be caused by a variety of means including trauma, diseases such as diabetes, herpes zoster and late-stage cancer, chemotherapy, or by a chemical injury. It is believed that neural pain circuits rewire themselves, both anatomically and biochemically, after nerve injury. In many patients suffering from damage to somatic sensory nerves, negative symptoms such as numbness are joined by positive sensations, involving a sort of false sensation of pain. The experience can range from mild dysesthesia to excruciating pain, rendering some patients unable to work, walk or do other daily activities.
In the past, patients were generally treated by administration of analgesics to relieve pain. A vast majority of such patients receive doses of these agents orally. Unfortunately, in some situations, oral administration of such agents has been associated with a variety of side effects, such as liver damage, kidney damage, gastrointestinal side effects, addiction, sedation, and/or weight gain which cannot be tolerated well by the patient. In other cases, malabsorption of oral preparations have resulted in subtherapeutic plasma levels. In other cases, the agents have relatively short plasma half-lives, necessitating inconveniently frequent dosing. In general, oral delivery involves a time delay as the analgesic is absorbed via the digestive system before entering the bloodstream. A number of agents which have traditionally been administered orally or by injection have been inappropriate or suboptimal for some patients when so-administered. There are a number of medications which, in at least some patients, are not tolerated well when orally administered (e.g. which cause undesirable gastrointestinal or other side effects) and/or which provide undesirably high or low concentrations or delayed concentrations in a target tissue. In some cases, dosages which are appropriate for oral administration, upon being distributed more or less uniformly throughout the body, are undesirably low in a particular area, e.g., tissue, to achieve desired results. Oral or injection administration may result in too slow or too rapid increase in blood plasma levels, e.g., may involve an undesirably long time delay as the analgesic is absorbed by the digestive system before entering the bloodstream, or may result in a xe2x80x9cspikexe2x80x9d in blood plasma levels followed by an undesirably low level, where a more constant level would be preferable. Some analgesics are particularly prone to cause or contribute to kidney or liver damage when administered orally.
Although other forms of delivery of pharmaceuticals agents are known, each has its drawbacks. Parenteral (i.e., intravenously or intramuscularly injected) administration is inconvenient and expensive, and is rarely used outside the hospital. Inhalation is believed to be not feasible with many analgesic agents currently in use. Therefore, there is a need for an analgesic delivery system which provides effective and acceptable levels, while preferably avoiding or reducing undesired effects such as liver damage or gastrointestinal side effects.
The present invention provides a transdermal composition for the treatment of pain in a subject, particularly a human subject. The transdermal composition for the treatment of pain in a subject includes an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound, e.g., a lecithin organogel carrier. In a preferred embodiment, the transdermal composition further includes an agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., a muscle relaxant, such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof. Preferably, the agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., the muscle relaxant, also has a biphasic solubility.
In one embodiment of the present invention, the amine containing compound having biphasic solubility is an antidepressant compound, such as a tricyclic antidepressant compound, e.g., doxepin or trimipramine.
In another embodiment of the present invention, the amine containing compound having biphasic solubility is a sodium channel blocker, a calcium channel blocker, an anti-epileptic compound, or an anti-convulsant compound.
Another embodiment of the invention features a transdermal composition which includes an amine-containing compound as described herein and an anti-inflammatory compound, such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx(copyright), and combinations thereof. Such a composition can further include an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant such as guaifenesin.
In another aspect, the invention features a transdermal composition for the treatment of pain in a subject including an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; a muscle relaxant in an amount effective to enhance the activity of the amine containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound having biphasic solubility and the muscle relaxant.
In yet another aspect, the invention features a transdermal composition for the treatment of pain in a subject including doxepin in an amount effective to treat pain in a subject; guaifenesin in an amount effective to enhance the activity of doxepin; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the doxepin and the guaifenesin.
Other aspects of the invention feature methods for treating pain in a subject in which the subject is contacted with a transdermal composition including an amine containing compound having biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound to thereby treat pain in the subject. In a preferred embodiment, the transdermal composition is applied to the skin of the subject.
Another aspect of the invention features a method for selecting a compound suitable for treating pain in a subject. The method includes transdermally administering an amine containing compound having biphasic solubility to a subject; and determining whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject. In a preferred embodiment, the method can further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program; and determining whether the three-dimensional chemical structure of the compound possesses sufficient characteristics to be useful as a sodium channel blocker or a calcium channel blocker, thereby selecting a compound suitable for treating pain in a subject.
In another aspect, the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound, e.g., a lecithin organogel carrier.
In yet another aspect, the invention features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.
In a further aspect, the present invention features transdermal compositions comprising lamotrigine and doxepin; topiramate and chlorzoxazone; topiramate and guaifenesin; topiramate and doxepin; topiramate and naproxen; doxepin and chlorzoxazone; lamotrigine and guaifenesin; lamotrigine, doxepin, and guaifenesin; or lamotrigine, doxepin, and chlorzoxazone.
Other features and advantages of the invention will be apparent from the following detailed description and claims.